The present invention relates to the use as medicaments of biphenyl compounds, the pharmaceutical compositions containing them, new biphenyl compounds, their preparation process and the intermediates of this process.
A subject of the invention is as medicaments the compounds of general formula (I): 
in which R1 and R2, identical or different, represent a hydrogen atom, a halogen atom, a hydroxyl radical, a trifluoromethyl radical, a nitro radical, an amino radical, an alkyloxy, alkylthio, alkylamino or dialkylamino radical, in which the alkyl contains from 1 to 8 carbon atoms, an xe2x80x94NRARB group, in which RA and RB form with the nitrogen atom to which they are linked a saturated or unsaturated heterocycle with 5 to 6 members optionally containing another heteroatom chosen from N, O and S, a linear or branched alkyl, alkenyl or alkynyl radical, each containing at most 8 carbon atoms and optionally substituted, an aryl radical containing from 6 to 14 carbon atoms and optionally substituted, an aralkyl radical containing from 7 to 15 carbon atoms and optionally substituted, or a CH(OH)xe2x80x94Y or C(O)xe2x80x94Y radical in which Y represents a substituted or non-substituted alkyl, alkenyl or alkynyl radical containing from 1 to 8 carbon atoms, or a substituted or non-substituted aryl group containing from 6 to 14 carbon atoms, or also R1 can form together with R3 a xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 group, R3 and R4, identical or different, represent a hydrogen atom, a halogen atom or an alkyl radical containing from 1 to 8 carbon atoms, or R3 can form together with R1 a xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 group, R6 and R7 identical or different, represent a hydrogen atom or a halogen atom, R8 represents a hydrogen atom or an optionally substituted benzyl radical and R5 represents an [A]xe2x80x94CH3, xe2x80x94[A]xe2x80x94C(OH)ZZxe2x80x2 or xe2x80x94[A]xe2x80x94C(O)Zxe2x80x3 group in which xe2x80x94[A]xe2x80x94 represents a linear or branched alkylene, alkenylene or alkynylene radical each containing at most 8 carbon atoms or a single bond, and Z, Zxe2x80x2 and Zxe2x80x3 represent a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms or an aryl radical containing from 6 to 14 carbon atoms and optionally substituted, as well as their addition salts with pharmaceutically acceptable acids and bases, it being understood that there are excluded the compounds in which R5 represents the [A]xe2x80x94C(O)xe2x80x94Zxe2x80x3 group in which [A] is a single bond, Zxe2x80x3 is an alkyl radical containing from 1 to 8 carbon atoms and R1, R2, R3, R4, R6, R7 and R8 are hydrogen atoms.
By halogen atom is meant fluorine, iodine, bromine and chlorine.
By alkyloxy radical containing from 1 to 8 carbon atoms, is preferably meant the radical chosen from methoxy, ethoxy, propoxy, butoxy and pentoxy.
By alkylthio radical containing from 1 to 8 carbon atoms, is preferably meant the radical chosen from methylthio, ethylthio, propylthio, isopropylthio and butylthio.
By alkylamino radical containing from 1 to 8 carbon atoms is preferably meant the radical chosen from methylamino, ethylamino, propylamino, butylamino, pentylamino.
By dialkylamino radical each containing from 1 to 8 carbon atoms is preferably meant the radical chosen from dimethylamino, diethylamino and methylethylamino.
By xe2x80x94NRARB group is preferably meant the group chosen from pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl and pyrrolyl.
By linear or branched alkyl, alkenyl or alkynyl radical, each containing at most 8 carbon atoms is preferably meant the radical chosen from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethyl pentyl, 3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl 3-ethylpentyl, vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl, isobutenyl, ethynyl, propynyl, propargyl, butynyl and isobutynyl and most particularly the methyl, ethyl, vinyl, propenyl, ethynyl and propynyl radical.
By aryl radical containing from 6 to 14 carbon atoms and aralkyl containing from 7 to 15 carbon atoms and optionally substituted, is preferably meant a phenyl or benzyl radical optionally substituted by a halogen atom chosen from fluorine, chlorine, bromine and iodine, an alkyl radical having from 1 to 8 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, an alkoxy radical having from 1 to 8 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, an alkylthio radical having from 1 to 8 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, an amino, alkylamino radical having from 1 to 8 carbon atoms such as methylamino or ethylamino, dialkylamino having 2 to 16 carbon atoms such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals being optionally in oxidized form, an aminoalkyl radical having from 1 to 8 carbon atoms such as aminomethyl or aminoethyl, a dialkylaminoalkyl radical having from 3 to 16 carbon atoms such as dimethylamino methyl or ethyl, a dialkylaminoalkyloxy radical having from 3 to 16 carbon atoms such as in particular the dimethylamino ethyloxy radical, a hydroxyl group, a free, esterified carboxy group such as alkoxy carbonyl for example methoxy carbonyl or ethoxy carbonyl or salified by a sodium or potassium atom, a cyano radical, a trifluoromethyl radical, a nitro radical, a formyl radical, a carbamoyl radical, an acyl group such as acetyl, propionyl, butyryl or benzoyl, acyloxy having up to 12 carbon atoms such as acetoxy or a group of formula: xe2x80x94Oxe2x80x94COxe2x80x94(CH2)mCO2H in which m is an integer ranging from 1 to 5, an alkenyl radical such as vinyl or propenyl, an alkynyl radical such as ethynyl or propynyl, an aryl radical such as phenyl, furyl, thienyl or aralkyl such as benzyl.
The expression xe2x80x9coptionally substituted arylxe2x80x9d indicates that one or more substituents, identical or different, can be present in the ortho, meta or para position.
When R1 and R2 are substituted alkyl, alkenyl or alkynyl radicals, they are the substituents as defined above.
The invention naturally extends to the salts of the compounds of formula (I), such as for example the salts formed when the compounds of formula (I) contain an amino function, with hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic acids such as methane or ethanesulphonic acids, arenesulphonic acids, such as benzene or paratoluene sulphonic acids and arylcarboxylic acids, or when the compounds of formula (I) contain an acid function, with the salts of the alkali or alkaline earth metals or ammonium optionally substituted.
A particular subject of the invention as medicaments is the compounds of formula (I) as defined previously corresponding to general formula (Ixe2x80x2): 
in which
either Rxe2x80x25 represents an xe2x80x94[A]xe2x80x94CHO radical as defined previously and R1, R2, R3, R4, R6, R7 and R8 are as defined previously, it being understood that when [A] represents a single bond and R3, R4, R6, R7 and R8 are hydrogen atoms, R1 and R2 cannot simultaneously represent a hydrogen atom,
or Rxe2x80x25 represents an xe2x80x94[A]xe2x80x94C(OH)ZZxe2x80x2 group as defined previously and R1, R2, R3, R4, R6, R7 and R8 are as defined previously, it being understood that when [A] represents a single bond and R3, R4, R6, R7, and R8 are hydrogen atoms, R1 and R2 cannot simultaneously represent a hydrogen atom,
or Rxe2x80x25 represents an xe2x80x94[A]xe2x80x94CH3 radical as defined previously and R1, R2, R3, R4, R6, R7 and R8 are as defined previously, it being understood that when R3, R4, R6, R7 and R8 are hydrogen atoms, R1 and R2 cannot simultaneously each represent a hydrogen atom, and it being understood that R1, R2, R3 or R4 cannot represent an alkyl radical or a halogen atom,
or Rxe2x80x25 represents an [A]xe2x80x94C(O)Zxe2x80x3 radical as defined previously, R1, R2, R3, R4, R6, R7 and R8 are as defined previously, it being understood that when [A] represents a single bond, R3, R4, R6, R7 and R8 are hydrogen atoms, and Zxe2x80x3 is an alkyl radical containing from 1 to 8 carbon atoms, so R1 and R2 cannot simultaneously each represent a hydrogen atom, or cannot represent a nitro or hydroxyl radical, as well as their addition salts with pharmaceutically acceptable acids and bases.
A more particular subject of the invention as medicaments is the compounds of general formula (Ixe2x80x2) as defined previously, in which R1, R2, R3, R4, R6, R7 and R8 are as defined previously and in which xe2x80x94[A]xe2x80x94 represents a single bond, as well as the addition salts with pharmaceutically acceptable acids or bases.
When Rxe2x80x25 represents an [A]xe2x80x94C(O)Zxe2x80x3 group, [A] is preferably a single bond. This is preferably a radical chosen from formyl, acetyl, propionyl, butyryl and benzoyl.
A quite particular subject of the invention as medicaments is the compounds of formula (Ixe2x80x2) as defined previously in which R1, R2, R3, R4, R6R7 and R8 have the same meaning as previously and in which Rxe2x80x25 represents a formyl radical as well as the addition salts with pharmaceutically acceptable acids or bases.
A quite particular subject of the invention is also as medicaments the compounds of formula (Ixe2x80x2) as defined previously in which R1, R2, R3, R4, R6, R7 and R8 have the same meaning as previously and in which Rxe2x80x25 represents an xe2x80x94[A]xe2x80x94C(OH)ZZxe2x80x2 group as defined previously, as well as the addition salts with pharmaceutically acceptable acids or bases.
When, Rxe2x80x25 represents an [A]xe2x80x94C(OH)ZZxe2x80x2 radical, [A] is preferably a single bond or an alkylene group of formula xe2x80x94(CH2)nxe2x80x94, in which n represents an integer comprised between 1 and 8, such as xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2CH2xe2x80x94, Z and Zxe2x80x2 preferably represent a hydrogen atom, an alkyl radical or a phenyl radical.
A most particular subject of the invention as medicaments is the compounds of formula (Ixe2x80x2) as defined previously in which Rxe2x80x25 represents a CH2OH radical and R1, R2, R3, R4, R6, R7 and R8 have the same meaning as previously as well as the addition salts with pharmaceutically acceptable acids and bases.
When Rxe2x80x25 represents an [A]xe2x80x94CH3 radical, [A] is preferably a single bond or a CH2, CH(CH3), C(CH3)2, CH2CH2, CH2CH2CH2 or CH2CH2CH2CH2 group.
A more particular subject of the invention is as medicaments the compounds of formula (Ixe2x80x2) as defined previously in which R6, R7 and R8 are hydrogen atoms.
A more particular subject of the invention is as medicaments the compounds of formula (Ixe2x80x2) as defined previously in which R6 and R7 are hydrogen atoms and R8 is a benzyl group.
A quite particular subject of the invention as medicaments is the compounds of formula (Ixe2x80x2) as defined previously in which R1 and R2 identical or different are halogen atoms and R3, R4, R6, R7 and R8 are hydrogen atoms.
A quite particular subject of the invention as medicaments is the compounds of formula (I) as defined previously corresponding to general formula (Ixe2x80x3): 
in which Rxe2x80x21 represents an aryl group containing from 6 to 14 carbon atoms and optionally substituted, Rxe2x80x22 represents a halogen atom, a nitro radical or an amino radical, as well as the addition salts with pharmaceutically acceptable acids and bases.
A quite particular subject of the invention as medicaments is the compounds of formula (I) as defined previously corresponding to general formula (Ixe2x80x3) as defined above in which Rxe2x80x21 represents a phenyl radical substituted by a dialkylaminoalkyloxy group having 3 to 16 carbon atoms and more particularly the dimethylaminoethyloxy radical, as well as the addition salts with pharmaceutically acceptable acids and bases.
A more specific subject of the invention as medicaments is the compounds of formula (I) as defined previously the names of which follow:
2,6-dibromo-4xe2x80x2-hydroxy-(1,1xe2x80x2-biphenyl)-4-methanol,
2,6-dichloro-4xe2x80x2-hydroxy-(1,1xe2x80x2-biphenyl)-4-methanol,
2,6-dinitro-4xe2x80x2-hydroxy-(1,1xe2x80x2-biphenyl)-4-methanol,
4,4xe2x80x3-dihydroxy-(1,1xe2x80x2:2xe2x80x2,1xe2x80x3-terphenyl)-5xe2x80x2-methanol,
1-[2-chloro-4xe2x80x2-hydroxy-3-methyl-6-(1-methylethyl))-(1,1xe2x80x2-biphenyl-4-yl)]-ethanone,
2-bromo-4xe2x80x2-hydroxy-6-nitro-(1,1xe2x80x2-biphenyl)-4-methanol,
1-[2-chloro-4xe2x80x2-hydroxy 3-methyl-6-(1-methylethyl)-(1,1xe2x80x2-biphenyl-4-yl)]-ethanol,
4xe2x80x2-hydroxy-2-trifluoromethyl-(1,1xe2x80x2-biphenyl)-4-methanol,
4xe2x80x2-methyl-2xe2x80x2-trifluoromethyl-(1,1xe2x80x2-biphenyl)-ol,
2,6-dichloro-4xe2x80x2-hydroxy-(1,1xe2x80x2-biphenyl)-4-carboxaldehyde,
2-chloro-4xe2x80x2-hydroxy-6-(1-methylethyl)-(1,1xe2x80x2-biphenyl)-4-methanol,
2-chloro-4xe2x80x2-hydroxy-6-trifluoromethyl-(1,1xe2x80x2-biphenyl)-4-methanol,
2,6-dichloro-4xe2x80x2-hydroxy-5xe2x80x2-(phenylmethyl)-(1,1xe2x80x2-biphenyl)-4-methanol,
2-bromo 6-[[4-[2-(dimethylamino) ethoxy] phenyl] hydroxymethyl] 4xe2x80x2-hydroxy (1,1xe2x80x2-biphenyl) 4-methanol,
[6-bromo 4xe2x80x2-hydroxy 4-(hydroxymethyl) (1,1xe2x80x2-biphenyl) 2-yl] [4-[2-(dimethylamino) ethoxy] phenyl] methanone,
6xe2x80x2-bromo 4-[2-(dimethylamino) ethoxy] 4xe2x80x3-hydroxy (1,1xe2x80x2:2xe2x80x2,1xe2x80x3-terphenyl) 4xe2x80x2-methanol,
4-[2-(dimethylamino) ethoxy] 4xe2x80x3-hydroxy 6xe2x80x2-nitro (1,1xe2x80x2:2xe2x80x2,1xe2x80x3-terphenyl) 4xe2x80x2-methanol,
6xe2x80x2-chloro 4,4xe2x80x3-dihydroxy (1,1xe2x80x2:2xe2x80x2,1xe2x80x3-terphenyl) 4xe2x80x2-methanol.
The Applicant has demonstrated that the compounds of formula (I) as well as their addition salts with pharmaceutically acceptable acids and bases are particularly useful products from a pharmacological point of view. They are original ligands of the oestrogen receptor.
As such, the products of formula (I) can be used in the treatment of disorders linked to hypofolliculinemia, for example, amenorrheas, dysmenorrheas, repeated abortions, premenstrual disorders, in the treatment of certain oestrogen-dependent pathologies such as prostatic adenomas or carcinomas, mammary carcinomas and their metastases or in the treatment of benign tumours of the breast, both as an antiuterotropic as well as in the replacement treatment of symptoms linked to the menopause and in particular of osteoporosis.
The invention extends to the pharmaceutical compositions containing at least one medicament as defined above as active ingredient.
The compounds of formula (I) are used by digestive, parenteral or local route, for example by percutaneous route. They can be prescribed in the form of simple or sugar-coated tablets, capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microspheres, implants, patches, which are prepared according to the usual methods.
The active ingredient or ingredients can be incorporated with excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersion or emulsifying agents, preservatives.
The dose varies according to the illness to be treated and the administration route: it can vary for example from 1 mg to 100 mg by day in adults by oral route.
Certain products of formula (I) are new and are therefore a subject of the present invention.
Others are known.
Certain products of general formula (I) with R5 representing an [A]xe2x80x94C(OH)ZZxe2x80x2 group and R1, R2, R3, R4, R6, R7 and R8 are hydrogens, are known as intermediate synthetic products or also in the field of liquid crystals. There can be mentioned the following examples:
Certain products of general formula (I) with R5 representing an [A]xe2x80x94CH3 group are used in the field of liquid crystals. There can be mentioned the following examples:
R1xe2x95x90Cl and R5=n-Pentyl, Liq. Cryst. 10(6), 799-802
R1xe2x95x90Me and R5=n-Pentyl, Liq. Cryst. 10(6), 799-802
R1xe2x95x90F, R2=F and R5=n-Pentyl, GB2257701 (Feb. 1, 1993)
R3xe2x95x90Cl and R5=n-pentyl, CA116-107805.
Certain products of general formula (I) with R5 representing an [A]xe2x80x94COZxe2x80x3 group containing from 2 to 8 carbon atoms are for their part used as synthetic intermediate products (CA 120 77179u R5=acetyl and R1xe2x95x90NO2) or also in the field of liquid crystals (CA 111 245029e R5xe2x95x90C(O)C5 and R1xe2x95x90OH).
Certain products of general formula (I) with R5 representing an [A]xe2x80x94CHO group and R1, R2, R3, R4, R5, R6, R7 and R8 are hydrogens are known as synthetic intermediate products or also in the field of liquid crystals. There can be mentioned the following example:
R5xe2x95x90CHO JP01207254 (1989).
Certain products of general formula (I) with R5 representing an [A]xe2x80x94COOH group are known. There can be mentioned the following example:
R5xe2x95x90xe2x80x94(CH2)nxe2x80x94COOH, n=0, 1 or 2 and R1xe2x95x90R2xe2x95x90I or Cl: A. Dibbo et al. J. Chem. Soc. (1961) 2890-2902.
Thus a subject of the invention is also the use, as a medicament, on the one hand of known products of general formula (I) and on the other hand of new products of general formula (I).
Therefore a subject of the invention is also new compounds of general formula (I) corresponding to formula (Ixe2x80x2) as described previously, as well as their addition salts with acids and bases.
A quite particular subject of the invention is the compounds of general formula (I) as defined previously listed above.
Another particular subject of the invention is new compounds of formula (I) as defined previously corresponding to general formula (Ixe2x80x3) as defined above as well as their addition salts with acids and bases.
A subject of the invention is also a preparation process for products of formula (Ixe2x80x2) as defined above characterized in that a product of formula (II): 
in which R1, R2, R3 and R4 are as defined previously and R5A has the values of Rxe2x80x25 as defined previously as well as the hydrogen or esterified or non esterified xe2x80x94[A]xe2x80x94CO2H values and X represents a hydrogen atom, halogen or an OSO2CF3 group, is subjected to the action, in the presence of a catalyst, of a product of formula (III): 
in which R6 and R7 are as defined previously, Y represents a hydrogen atom, halogen, a B(OH)2 group or an Sn(R)3 group, in which R represents an alkyl group containing from 1 to 8 carbon atoms, and P represents a protective group, in order to obtain a product of formula (IV): 
in which P, R1, R2, R3, R4, R5A, R6 and R7 have the same meaning as previously, which product of formula (IV) if desired or if necessary is subjected in an appropriate order to one or, if appropriate, several of the following reactions in order to obtain the product of formula (Ixe2x80x2):
deprotection of the phenol,
debenzylation then rearrangement in order to obtain a product of formula (I) with R8=benzyl,
total or partial reduction of the NO2 groups which can be represented by R1 or R2 into NH2,
substitution of NH2 which can be represented by R1, R2, R3 or R4, by Br or by I,
formylation reaction when R5A represents a hydrogen atom,
reduction of the esterified xe2x80x94[A]xe2x80x94CO2H function which can be represented by R5A,
saponification,
reduction of the xe2x80x94[A]xe2x80x94CHO group which can be represented by R5A into an xe2x80x94[A]xe2x80x94CH2OH group,
oxidation of the xe2x80x94[A]xe2x80x94CHO group which can be represented by R5A into an xe2x80x94[A]xe2x80x94CO2H group,
esterification of the xe2x80x94[A]xe2x80x94CO2H group which can be represented by R5A,
reduction of the acyl function which can be represented by R5A into the corresponding alcohol, or into the corresponding alkyl radical,
Wittig""s reaction on the [A]xe2x80x94CHO function which can be represented by R5A in order to obtain an [A]xe2x80x94CHxe2x95x90CHxe2x80x94CHO group, then reduction of the unsaturated aldehyde in order to obtain the corresponding alcohol of formula [A]xe2x80x94CHxe2x95x90CHxe2x80x94CH2OH,
Wittig""s reaction on the [A]xe2x80x94CHO function which can be represented by R5A in order to obtain an [A]xe2x80x94CH2xe2x80x94CHO group, then reduction of the [A]xe2x80x94CH2xe2x80x94CHO aldehyde in order to obtain the corresponding alcohol of formula [A]xe2x80x94CH2xe2x80x94CH2OH,
reduction reaction when [A] represents a bivalent alkenylene or alkynylene radical,
action of an organometallic on the aldehyde, the ketone or the esterified acid which can be represented by R5A,
formation of a pyrrole group from NH2,
substitution of NH2 by an S-Alkyl group, and salification by an acid or a base.
Formation of the biphenyls of formula (IV) by coupling of the aromatic compound of formula (II) with the aromatic compound of formula (III) is carried out either in the presence of a catalyst chosen from palladium derivatives in the case where:
(a) Y represents a B(OH)2 or Sn(R)3 group and X represents an OSO2CF3 group, a bromine atom or an iodine atom,
and thus can be carried out under the conditions described in the following articles when Y represents a B(OH)2 group:
A. Huth, I. Beetz and I. Schumann Tetrahedron (1989) 45 6679: Conditions: Na2CO3 2M/Pd(P"PHgr"3)4/Toluene/LiCl/EtOH/xcex94
J. K. Stille et al. Ang. Chem. Int. Ed. (1986) 25 508: Conditions: Pd(P"PHgr"3 )4/LiCl/Dioxane/xcex94
T. Oh-e, N. Migawa and A. Suzuki J. Org. Chem. (1993) 58 2201-2208: Conditions: K3PO4/KBr/Pd(P"PHgr"3 )4/Dioxane/xcex94
Suzuki et al., Synlett (1992) 208
Conditions: Pd(P"PHgr"3)4/Ba(OH)2/DMEaq;
or also when Y represents an SnBu3 group, under the conditions described in the following articles:
J. K. Stille et al, J. Am. Chem. Soc. (1987) 5478-5480 or by V. Farina, J. Org. Chem. (1993) 58 5434;
or in the presence of copper in the case where:
(b) Y represents an iodine atom and X represents a chlorine atom,
(c) Y represents a chlorine atom and X represents an iodine atom,
and thus can be carried out under the conditions described in the following:
P. E. Fanta Chem. Rev. (1964) 38 139 or synthesis (1974) 9: Conditions: Cu/DMF/120xc2x0 C.;
or in the presence of a strong base and of ZnCl2 then a catalyst chosen from palladium derivatives in the case where:
(d) Y represents a bromine atom and X represents a hydrogen atom,
(e) Y represents a hydrogen atom and X represents a bromine atom,
and thus can be carried out under the following conditions:
1) nBuli/THF/xe2x88x92768xc2x0 C.
2) ZnCl2 
3) ArBr/Pd(P"PHgr"3)4/xcex94
4) HCl/MeOH.
The orthometalation reactions are described for example in the following documents:
T. KRESS Synthesis (1983) 803,
N. IWAO J. Org. Chem. (1990) 55 3623.
Moreover, the exchange reaction with ZnCl2 followed by a coupling reaction has been described by E. Negishi in J. Org. Chem. (1977) 42 182.
The protective group P preferably represents an alkyl radical containing from 1 to 4 carbon atoms, a benzyl group, an RCRDRESi group, in which RC, RD and RE identical or different, independently of one another each represent an alkyl radical containing from 1 to 4 carbon atoms or a phenyl group. This is most particularly the Si(Me)2C(Me)3 or xe2x80x94Si(Ph)2C(Me)3 groups.
Deprotection reactions are the standard deprotection methods known to a person skilled in the art. A fairly complete review is provided in the following work: Protective groups in organic synthesis, T. W Greene, John Wiley and sons (1981).
As an example the deprotection reactions when P is a methyl radical can be carried out by the action of tribromoborane in dichloromethane or hydrochloric acid in pyridine, the deprotection reactions when P is a benzyl group can be carried out by the action of hydrogen in the presence of palladium on carbon in ethyl acetate, by the action of trifluoroacetic acid or by the action of trimethylsilyl iodide. The deprotection reactions when P is a tertbutyldiphenylsilyl group can be carried out by the action of tetrabutyl ammonium fluoride (TBAF) in solution in tetrahydrofuran.
At the time of the debenzylation reaction by the action of trifluoroacetic acid, a rearrangement and formation of a deprotected derivative with R8=benzyl can be obtained.
The reduction reaction of the NO2 radical which can be represented by R1 or R2 into an NH2 radical can be carried out by the action of tin dichloride in ethanol under reflux and the monoreduction reaction is preferably carried out by the action of cyclohexene in the presence of palladium dihydroxide in ethanol or tetrahydrofuran under reflux.
The substitution reaction of NH2 which can be represented by R1 or R2 by Br is preferably carried out by the action of hydrobromic acid in the presence of sodium nitrite and of copper bromide in water at 0xc2x0 C. or by the action of tribromomethane in the presence of terbutylnitrite.
The substitution reaction of NH2 by iodine is preferably carried out by the action of potassium iodide in the presence of sodium nitrite and sulphuric acid or by the action of iodine in the presence of terbutylnitrite.
The formylation reaction when R5A is a hydrogen atom can be carried out in the presence of dimethylformamide and a strong base such as n-butyllithium then hydrolysis with a mineral acid such as hydrochloric acid.
The reduction reaction of the esterified xe2x80x94[A]xe2x80x94CO2H function which can be represented by R5A in order to obtain the corresponding alcohol is carried out for example by the action of lithium aluminium hydride in tetrahydrofuran.
There is particularly meant by esterified xe2x80x94[A]xe2x80x94CO2H, the xe2x80x94CO2Me and xe2x80x94CO2Et groups.
The saponification reaction of the ester function which can be represented by R5A into the corresponding acid is carried out for example by the action of an alkaline base such as soda or potash in tetrahydrofuran or a lower alcohol such as methanol or ethanol.
The reduction reaction of the [A]xe2x80x94CHO group which can be represented by RSA into an [A]xe2x80x94CH2OH group is carried out for example by the action of sodium borohydride in methanol at 0xc2x0 C. or by the action of hydrogen in the presence of palladium on carbon in ethyl acetate.
The oxidation reaction of the [A]xe2x80x94CHO group which can be represented by R5A into an [A]xe2x80x94CO2H group can be carried out by the action of Jones reagent (chromic acid/sulphuric acid) in a neutral solvant such as acetone, by the action of silver oxide in tetrahydrofuran and 2N soda or by the action of sodium hypochlorite in the presence of aminosulphonic acid.
The esterification reaction of the xe2x80x94[A]xe2x80x94CO2H group which can be represented by R5A, can be carried out by the action of ethanol or methanol in the presence of a strong acid such as hydrochloric or sulphuric acid.
The reduction reaction of the [A]xe2x80x94C(O)xe2x80x94Zxe2x80x3 group which can be represented by R5A into the corresponding alcohol can be carried out for example by the action of sodium borohydride in methanol.
The reduction reaction of the [A]xe2x80x94C(O)xe2x80x94Zxe2x80x3 group which can be represented by R5A into the corresponding alkyl can be carried out by the action of hydrogen in the presence of palladium on carbon in ethyl acetate.
Wittig""s reaction on the [A]xe2x80x94CHO function which can be represented by R5A in order to obtain an [A]xe2x80x94CHxe2x95x90CHxe2x80x94CHO group, is carried out by the action of phosphine "PHgr"3Pxe2x95x90CHxe2x80x94CHO.
The reduction of the unsaturated aldehyde [A]xe2x80x94CHxe2x95x90CHxe2x80x94CHO in order to obtain the corresponding alcohol of formula [A]xe2x80x94CHxe2x95x90CHxe2x80x94CH2OH can be carried out by the action of the sodium borohydride in the presence of CeCl3, 7H2O in methanol.
Wittig""s reaction on the [A]xe2x80x94CHO function which can be represented by R5A in order to obtain an [A]xe2x80x94CH2xe2x80x94CHO group (homologation reaction) is carried out by the action of phosphine "PHgr"3Pxe2x80x94CH2OMe or "PHgr"2P(O)xe2x80x94CH2OMe.
The reduction of the aldehyde [A]xe2x80x94CH2xe2x80x94CHO in order to obtain the corresponding alcohol of formula [A]xe2x80x94CH2xe2x80x94CH2OH can be carried out by the methods described above.
The total or partial reduction reaction when [A] represents a bivalent alkenylene or alkynylene radical can be carried out either totally by the action of hydrogen in the presence of a catalyst such as palladium on carbon or a rhodium catalyst such as Wilkinson""s reagent or partially (alkynylene becomes alkenylene) by the action of a poisoned catalyst such as palladium on barium sulphate.
The action of an organometallic on the aldehyde, the ketone or the esterified acid which can be represented by R5A provides access to the products of formula (Ixe2x80x2) in which Rxe2x80x25 represents xe2x80x94[A]xe2x80x94C(OH)ZZxe2x80x2, Z and Zxe2x80x2 represents an optionally substituted alkyl, alkenyl, alkynyl or aryl radical.
The organometallic derivative of a phenyl, alkyl, alkenyl or alkynyl radical is chosen from the magnesium compounds of formula AlkMgHal or ArMgHal and the lithium compounds of formula AlkLi or PhLi in which Alk represents an alkyl, alkenyl or alkynyl group containing at most 8 carbon atoms. Ar represents an optionally substituted phenyl and Hal represents a halogen atom. In a preferred implementation of the process, Hal represents a chlorine, bromine or iodine atom, preferably bromine. The reaction medium can then be subjected to a strong acid such as hydrochloric acid or sulphuric acid.
For example the action of Zxe2x80x94MgBr on the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90CHO provides access to the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90xe2x80x94CH(Z)xe2x80x94OH.
For example the action of PhMgBr on the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90CHO provides access to the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90xe2x80x94CH(Ph)xe2x80x94OH.
For example, the action of Zxe2x80x94MgBr on the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90COCH2CH3 provides access to the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90xe2x80x94C(OH)(Z)(Et).
For example, the action of PhMgBr on the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90COCH2CH3 provides access to the compounds of formula (Ixe2x80x2) in which Rxe2x80x25xe2x95x90xe2x80x94C(Ph)(Et)xe2x80x94OH.
For example, the action of MeMgBr on the compounds of formula (IV) in which R5Axe2x95x90CO2Me provides access to the compounds of formula (IV) in which R5Axe2x95x90xe2x80x94C(Me)2xe2x80x94OH.
The formation of an unsaturated heterocycle such as pyrrole from the corresponding amine is carried out by the action of 2,5 dimethoxytetrahydrofuran in the presence of acetic acid.
The substitution reaction of an amine by S-Alkyl is carried out by the action of (Alkyl-S)2 in the presence of tBuNO2.
Salification can be carried out under the usual conditions. The operation is carried out for example in the presence of ethanolic soda. A sodium salt can also be used such as the carbonate or the carbonate acid of sodium or of potassium.
Similarly, salification by an acid is carried out under the usual conditions. The operation is carried out for example with hydrochloric acid, for example in an ethereal solution.
A particular subject of the invention is a preparation process for products of formula (Ixe2x80x3) as defined above characterized in that a compound of formula (VII): 
in which Alkxe2x80x2 and Pxe2x80x2 identical or different, each represent an alkyl radical containing from 1 to 4 carbon atoms and Rxe2x80x21 and Rxe2x80x22 are as defined previously, is subjected to the action of a deprotection or reducing reagent of the ester function in order to obtain the product of formula (Ixe2x80x3) then, if desired, is subjected to the action of a base or an acid in order to obtain the corresponding salts.
This product of formula (VII) corresponds to products of formula (IV) in which P represents an alkyl radical containing from 1 to 4 carbon atoms, R2, R3, R4, R6, R7 and R8 are hydrogen atoms, R1 represents an optionally substituted aryl radical and R5A represents an esterified xe2x80x94CO2H group.
A process for the formation of products of formula (VII), with Rxe2x80x21 representing a Phxe2x80x94OH group, P and Alk representing a methyl, is described in the following reference:
J. Med. Chem. (1989) 32 1814-1820.
By analogy, this process can thus be extended to all the products of formula (V) with Rxe2x80x21 representing an optionally substituted aryl group containing from 6 to 14 carbon atoms.
Thus a compound of formula (V): 
in which Rxe2x80x21 represents an optionally substituted aryl group and Pxe2x80x2 represents an alkyl radical containing from 1 to 4 carbon atoms, is subjected to the action of a compound of formula (VI): 
in which Alkxe2x80x2 represents an alkyl radical containing from 1 to 4 carbon atoms and Rxe2x80x22 is as defined previously, in order to obtain a compound of formula (VII).
The action of the alkylcoumarate of formula (VI) on the compound of formula (V) in order to obtain the compound of formula (VII) is preferably carried out under nitrogen pressure at a temperature of 250xc2x0 C. in toluene. This reaction is described in the following reference: J. Med. Chem. (1989) 32 1814-1820.
The products of formula (V) are known or are easily accessible to a person skilled in the art by applying the general principles of functionalization of aromatic compounds. There can be mentioned as examples a few references:
W09309079 (Rxe2x80x21xe2x95x90Ph and Pxe2x80x2xe2x95x90Me), J. Organomet. Chem. 395(2), 277-9 (Rxe2x80x21xe2x95x90Phxe2x80x94OCH2CH2NMe2 and Pxe2x80x2xe2x95x90Me,).
The products of formula (VI) with Rxe2x80x22xe2x95x90H, are also known. There can be mentioned the following reference: J. Med. Chem. (1989) 32 1814-1820.
The products of formula (VI) with Rxe2x80x22 different from H, are known or easily accessible to a person skilled in the art. For example, the products of formula (VI) with Rxe2x80x22xe2x95x90Cl are formed by action of N-chlorosuccinimide on the product of formula (VI) with Rxe2x80x22xe2x95x90H.
The products of general formula (II) are en general connus or are accessibles to a person skilled in the art by applying the general principles of functionalization of aromatic compounds.
The products of formula (II) with Xxe2x95x900Tf (triflates) are obtained from the corresponding alcohols of general formula (IIxe2x80x2): 
by the action of triflic anhydride action in pyridine at 0xc2x0 C. according to the method described by Scott W. J., Stille J. K., J. Am. Chem. Soc. (1986) 108 3033.
The products of general formula (IIxe2x80x2) are for their part generally known to or are accessible by a person skilled in the art by applying the general principles of the chemistry of aromatic compounds. There can be mentioned among others the following reference: RODD""S CHEMISTRY OF CARBON COMPOUNDS Vol III Aromatic compounds Ed. M. F. ANSELL Elsevier Scientific Publishing Company (1981).
The products of formula (II) with X=I (iodated products) can be obtained by orthometallation from the corresponding non-iodated aromatic products of general formula (IIxe2x80x3): 
in particular by the action of N-iodosuccinimide or iodine in the presence of a strong base such as n-Butyllithium in tetrahydrofuran at xe2x88x9278xc2x0 C.
The products of general formula (IIxe2x80x3) are for their part generally known to or are accessible by a person skilled in the art by applying the general principles of the chemistry of aromatic compounds.
In the case where R5A is an xe2x80x94[A]xe2x80x94CO2H, [A]xe2x80x94C(O)Zxe2x80x3 or xe2x80x94[A]xe2x80x94C(OH)ZZxe2x80x2 group it will be necessary to provide the adequate protections known to a person skilled in the art in particular during the preparation of the products of general formula (II) from products of general formulae (IIxe2x80x2) and (IIxe2x80x3). As an example, the xe2x80x94[A]xe2x80x94CO2H group can be esterified, the formyl or acyl group can be protected in the form of an acetal such as dioxolane by the action of glycol in the presence of paratoluene sulphonic acid, the hydroxyl group can be protected in the form of a tetrahydropyrranyloxy group (OTHP) by the action of dihydropyrrane.
The products of formula (III) are known or accessible from protected parabromophenol or from parabromoanisole by the following methods: The products of formula (III) with Y representing the B(OH)2 group and P representing a methyl radical can first be obtained by the action of parabromoanisole with Mg turnings in anhydrous diethyl ether under reflux, then by the action of triethylborate in anhydrous diethyl ether at xe2x88x9270xc2x0 C., then hydrolysis with a strong mineral acid such as sulphuric acid.
The products of formula (III) with Y representing the B(OH)2 group can also be obtained by the action of parabromophenol protected by a protective group P such as benzyl or terbutyldiphenyl silyl, with triethylborate in the presence of n-butyllithium in tetrahydrofuran at xe2x88x9278xc2x0 C. followed by hydrolysis with a strong mineral acid such as sulphuric acid or with water.
The products of formula (III) with Y representing the SnBu3 group can be obtained by the action of parabromophenol protected by a protective group P such as tertbutyldiphenylsilyl, with tin tributyl chloride in the presence of n-butyllithium in tetrahydrofuran at xe2x88x9278xc2x0 C.
The products of formula (III) with Y representing an iodine atom and P representing a benzyl or terbutyldiphenylsilyl group can be obtained by the action of paraiodophenol with a protective group as defined above.
A subject of the invention is also as new industrial products and in particular new intermediates necessary for the implementation of the invention, the products of general formula (IV) with the exception of the product of formula (IV) in which R5A represents an esterified or non esterified [A]xe2x80x94CO2H radical.
The following examples illustrate the invention without however limiting it.
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether is added dropwise under reflux to a suspension, under inert gas, of 1.3 g of magnesium turnings in 5 ml of anhydrous diethyl ether, and the mixture is left under reflux for 2 hours. The reaction medium is then poured into a solution of 9.02 ml of triethylborate in 60 ml of anhydrous ether cooled down to xe2x88x9270xc2x0 C. After agitation for 1 hour at xe2x88x9270xc2x0 C., then for 1 hour at ambient temperature, the solution is poured into a mixture comprising 11 ml of sulphuric acid and 50 g of ice and water followed by agitation for 1 hour. The organic phase is extracted with 100 ml of an aqueous solution saturated in sodium bicarbonate, the aqueous phases are combined, then reacidified with 6N hydrochloric acid, extracted with ether, dried and evaporated under reduced pressure. 3.9 g of expected product is obtained.
I.R. spectrum: (Nujol)
Complex absorption OH/NH region, 1609, 1573 and 1518 cmxe2x88x921 NMR (DMSO-d6, 300 MHz)
Stage A: 1-bromo-4-(phenylmethoxy)-benzene
15.26 g of 50% sodium hydride in oil is added, at 0xc2x0 C., to a solution under inert gas of 50 g of parabromophenol in 320 ml of dimethylformamide, followed by agitation for 30 minutes at 0xc2x0 C., then 37.7 ml of benzyl bromide is added. Agitation is carried out for 2 hours 30 minutes while allowing the temperature to return to 20xc2x0 C., then the reaction mixture is poured into ice-cooled water, the precipitate is filtered and dried. 73.35 g of expected product is obtained.
Rf: 0.85 (thin layer chromatography, support: silica, eluant:
cyclohexane/ethyl acetate 7/3).
I.R. spectrum: (CHCl3)
Absence of OH
Aromatic 1592, 1580 and 1488 cmxe2x88x921 
Stage B: [4-(phenylmethoxy)phenyl]-boronic acid
143 ml of a solution of n-Butyllithium is added, dropwise, under inert gas and at xe2x88x9278xc2x0 C., to 47.08 g of the product obtained in Stage A in 375 ml of tetrahydrofuran, agitation is carried out for 1 hour, then 36.5 ml of triethylborate is added. Agitation is carried out for 14 hours, while allowing the temperature to return to 20xc2x0 C., and the reaction medium is hydrolyzed using a solution of ice-cooled water containing 45 ml of concentrated sulphuric acid, for 1 hour at 20xc2x0 C. The aqueous phase is extracted with ethyl acetate, the organic phases are washed with 2N soda and the aqueous phase is acidified to pH=1 using a solution of IN hydrochloric acid in order to precipitate the boronic acid. After filtration and drying the precipitate 28.54 g of expected product is obtained.
Rf: 0.16 cyclohexane/ethyl acetate 7/3)
I.R. spectrum: (Nujol)
Stage A: 1-Bromo-4-[[(1,1-dimethylethyl)diphenylsilyl]oxy]benzene
400 ml of dimethylformamide, 31.18 g of imidazole and 125.89 g of 1,1-dimethyl-ethyldiphenyl-chlorosilane are added under an inert atmosphere and at ambient temperature to 80.89 g of parabromophenol, then the solution obtained is agitated for 2 hours. The reaction medium is poured into 2 litres of water, precipitation is observed, the solid is solubilized with ethyl acetate and the aqueous phase is extracted with ethyl acetate, the combined organic phases are dried and evaporated under reduced pressure until an oil is obtained. Pentane is added and crystallisation is observed. After filtration and drying of the precipitate 179.24 g of expected product is obtained. Rf: 0.53 (thin layer chromatography, support: silica, eluant Cyclohexane/AcOEt 95/5).
Melting point: 56xc2x0 C.
NMR (CDCl3, 300 MHz)
Stage B: [4-[[(1,1-dimethylethyl)diphenylsilyl]oxy] phenyl]-boronic acid
60 ml of a solution of n-butyl-lithium is added, dropwise, at xe2x88x9278xc2x0 C. and under inert gas, to a solution of 30 g of the product of the previous stage in 100 ml of anhydrous tetrahydrofuran, followed, after agitation for 30 minutes at xe2x88x9278xc2x0 C., by the addition of 9.95 ml of trimethylborate. After agitation for 2 hours 30 minutes, while allowing the reaction medium to return to ambient temperature, 20 ml of water is added dropwise and agitation is carried out for 72 hours. After evaporation of the tetrahydrofuran under reduced pressure, the aqueous phase is extracted with ether, dried and concentrated under reduced pressure until an oil is obtained (26.35 g) which is purified by filtration chromatography on silica with a hexane/ethyl acetate mixture 1/1 in order to obtain 7.73 g of expected product in the form of the trimer and the monomer.
123.89 ml of a solution of sec-butyl-lithium (1.13 M) is added, dropwise, at xe2x88x9250xc2x0 C. and under inert gas, to a solution of 50 g of the product of Stage A of Preparation 3 in 300 ml of anhydrous tetrahydrofuran, then after agitation for 1 hour at xe2x88x9250xc2x0 C., 36.29 ml of tributyl tin chloride is added. After agitation for 30 minutes, while allowing the reaction medium to return to ambient temperature, the reaction mixture is poured into ice-cooled water, the aqueous phase is extracted with ethyl acetate, dried and evaporated to dryness under reduced pressure. 38.5 g of the product is obtained in the form of an oil (Tbp: 230xc2x0 C. under 10xe2x88x922 mbar)
Rf: 0.36 cyclohexane.
IR (CHCl3)
Aromatic 1569, 1583, 1510, 1493 cmxe2x88x921 
387 mg of imidazole and 411 mg of tertbutyldimethylsilyl chloride is added at ambient temperature and under an inert atmosphere to 500 mg of para-iodo-phenol in 4 ml of dimethylformamide and the mixture is maintained under agitation for 15 hours at ambient temperature then for 1 hour at 40xc2x0 C. The reaction medium is poured into water, and the aqueous phase is extracted with dichloromethane. The organic phase is then dried and evaporated under reduced pressure. In this way 636 mg of expected product is obtained.
Rf=0.82 cyclohexane/acetate ethyl 9/1).
NMR (CDCl3) 200 MHz
2.4 g of 50% sodium hydride in oil is added at 0xc2x0 C. and under an inert atmosphere to 10 g of para-iodo-phenol in 150 ml of dimethylformamide, the mixture is maintained under agitation for 30 minutes and 5.9 ml of benzyl bromide is added. After agitation for 30 minutes while allowing the reaction medium to return to ambient temperature, the reaction medium is poured onto ice and a precipitation of the product is observed. After drying, 14.7 g of expected product is obtained.
Rf=0.67 cyclohexane/ethyl acetate 9/1).
NMR (CDCl3) 200 MHz
14.73 ml of triflic anhydride is added, under inert gas and at 0xc2x0 C., to 19.0 g of 3,5-dibromo-4-hydroxy-benzaldehyde in 100 ml of pyridine. Agitation is carried out for 1 hour while allowing the temperature to return to ambient, the reaction medium is poured into water and the aqueous phase is extracted with 3 times 150 ml of dichloromethane. The organic phases are dried and evaporated to dryness under reduced pressure. 23.83 g of crude product is obtained which is purified by filtration chromatography using a cyclohexane/ethyl acetate mixture 1/1 as eluant. In this way 23.83 g of expected product is obtained. Rf: 0.71, cyclohexane/ethyl acetate 1/1. The operation is carried out in an equivalent manner for the preparation of the following triflates of general formula II